Drug toxicity in humans can result from causes such as therapeutic misadventure, illicit drug ingestion, or suicide attempt. Drug toxicity is a major health care problem throughout the world and results in significant financial costs as well as potential harm including possible death. Unfortunately, the vast majority of life-threatening drug intoxications do not have specific pharmacological antidotes to ameliorate their physiological effects. Other than providing supportive therapy to affected individuals, often little can be done to help individuals affected by most drug intoxications. Drug toxicity can also be a problem in veterinary medicine.
When a chemical, such as xenobiotic, is administered to an organism, two events must generally occur for a biological response to be triggered. First, the xenobiotic must be transported to the site of action (the “target site”). Second, after arriving at the target site, the xenobiotic must interact with the intended target in an appropriate manner. Interaction of a xenobiotic with the target site is governed largely by two factors:
a. the size and shape of the xenobiotic which controls how well the xenobiotic interacts with the target site; and
b. the nature and relative positions of appropriate functional groups of the xenobiotic which affects the type and strength of its interaction with complementary groups of the receptor.
Many physicochemical properties can be used to model receptor interaction. For example, molar volume (MV) is an overall measure of molecular size, while the energy of the lowest unoccupied molecular orbital (ELUMO) is a crude measure of the electron-accepting ability of a given chemical compound.
Several methods for treating various drug intoxications currently exist. Immunotoxicotherapy can produce purified drug-specific antibodies to treat some potentially fatal cases of drug poisoning. By linking the toxic drug to albumin and using it as a hapten, high affinity antibodies with excellent specificity can be theoretically formed for use against a particular molecule or a class of molecules. The last several years have brought major innovations in the safety and efficacy of immunotoxicotherapy. In addition, advances have occurred in the processes of fragmentation which permits a greater volume of distribution (VOD) and diminished risk of sensitization and enhanced renal elimination.
Volume of distribution is defined as the volume of fluid that would be necessary to contain the amount of drug in the body at a uniform concentration equal to that in plasma. Thus, the definition assumes the body is a single homogeneous fluid compartment and the drug is evenly distributed throughout. The VOD may exceed the actual volume of the body. In application, VOD defines the concentration following one intravenous dose and roughly describes tissue penetration. A large VOD indicates good tissue penetration, while a small VOD indicates poor tissue penetration.
The binding portion of the antibody, known as the Fab fragment, has been found to reduce the physiological effects of drugs, such as digoxin, PCP, cocaine, colchicine, and tricyclic antidepressants in various animal models. However, despite these reported advances and the purported potential advantages of antibody use over other drug intoxication therapies, only one commercial antibody product is currently available to treat drug overdoses in humans. Digibind®, a digoxin immune Fab, is a lyophilized powder of antigen binding fragments (Fab) derived from specific antibodies raised from sheep. It has been shown to be highly effective in treating the life threatening cardiotoxic effects of digoxin, an inhibitor of the myocardial Na+/H+ ATPase pump.
A number of reasons explain the lack of widespread immunotoxicotherapy use in humans. First, there is no guarantee that a specific antibody can be produced that can effectively bind to a given target toxic drug molecule or its associated class of molecules. In addition, since antibodies are directed at specific chemical moieties, antibodies cannot offer broad substrate detoxification to an entire class of intoxicants.
Moreover, the ability and capacity of antibodies to effectively bind drug toxins is severely limited by each antibody's stoichiometry. One Fab fragment can typically bind only one target molecule. This property limits the binding effectiveness of these antibodies, especially for drug toxicities that typically include large doses and extensive tissue and plasma protein binding (e.g., amiodarone).
Immunotoxicotherapy has also been shown to be only effective in situations where the amount of toxic drug in the bloodstream is relatively small and protein and tissue binding is not significant. An example of a drug suitable for immunotoxicotherapy is the drug digoxin. The plasma concentration of digoxin that begins to cause cardiac toxicity is approximately 1.7 ng/ml, with only approximately 25±5% of it being bound in plasma. In contrast, the same toxic plasma concentrations for the drugs amiodarone and amitriptyline begin at approximately 3,500 ng/ml and 1,000 ng/ml, respectively, corresponding to 99.98±0.01% and 94.8±0.8% drug binding in plasma, respectively. This fact largely explains why antibodies are more effective against drugs such as digoxin which cause toxicity at low concentrations (approximately 1 nM).
In addition, most antibodies that have been produced have been formed for use against toxic drug molecules in humans were isolated from animals (e.g. Digibind® is produced from sheep antibodies). Therefore, there remains a potential risk of allergy and aphylactic shock, because the Fc portion of the antibody, which is the most antigenic portion of the antibody, is cleaved from the binding portion of the immunoglobulin (Fab fragment) using papain. Also, unless major advances are made in the molecular production of antibodies, particularly human monoclonal antibodies, the quantity of antibodies which can be formed is very limited. Consequently, it is extremely expensive and impractical to manufacture the large quantities of antibodies required to treat drug toxicities involving drugs that are highly protein and tissue bound as well as toxicities arising from drugs having relatively high toxic blood concentrations.
Even for a drug like digoxin that causes drug toxicity at much lower concentrations than do drugs such as amiodarone and amitriptyline and is much less protein bound, the cost of treatment can still be prohibitive. For example, depending upon the blood concentrations of digoxin, 10-20 vials or more of Digoxin immune Fab (ovine), trade named Digibind®, may be required to effectively treat a 70 kg (155 pound) individual. This can translate to a cost of approximately $10,000 to $30,000. Accordingly, the cost of using an agent such as Digibind® can be prohibitively expensive where the potency of the drug is much lower and consequently a much greater amount of toxic drug (e.g., amiodarone or amitriptyline) would be required to be bound by the antibody.
Therefore, in the current state of development, antibodies are not a viable option to treat the vast majority of drug overdoses. Furthermore, even if new advances in molecular medicine allowed human-derived antibodies to be produced in mass quantities at a reasonable cost, their slow onset time of actions in humans is another limiting factor. For example, the median time to initial response for Digibind® is reported to be 19 minutes. Only 75% of patients showed evidence of response within 60 minutes. Slow response combined with inability to provide broad substrate detoxification and high cost are expected to continue to make antibodies a poor choice for the treatment of drug toxicity.
Another method for reducing toxic drug effects is infusion of enzymes into the blood. This method may be feasible to ameliorate toxic in-vivo effects of drugs. Specifically, the acute physiological effects of cocaine in various animal species have been reported to be acutely ameliorated using animal and human butyrylcholinesterase, the principal esterase in the blood that degrades cocaine to its major metabolites.
While sometimes effective, this approach suffers from a number of drawbacks. First, water-soluble plasma enzymes, such as butyrylcholinesterase, do not metabolize the majority of drugs. Second, infusion of enzymes directly into the blood does not permit the beneficial and synergistic actions of initially partitioning the drug at high local concentrations in an environment containing high concentrations of an enzyme. The reaction velocity (V) of enzymes generally obey Michaelis-Menten kinetics. Thus, although V is proportional to the substrate concentration at low concentrations (first order) the reaction velocity is constant at higher substrate concentrations (zero order). Zero order kinetics largely negates the potential treatment advantage derived from having a high local enzyme concentration.
Although the infusion of water soluble enzymes, such as butyrylcholinesterase, into the blood can cause rapid and efficient conversion of ester-type drugs, this approach is not applicable for P450 microsomal fractions. P450 microsomal fractions require a lipid environment and are extensively integrated into the cellular membranes of hepatocytes and other cells.
Another method for detoxifying drugs is hemodialysis. Hemodialysis can be used to detoxify the blood stream from various drugs and metabolic disorders using hemoperfusion and hemodialysis. However, for a number of reasons, this method is not appropriate for the vast majority of life threatening drug overdoses.
First, many drugs that cause toxicity in humans are not susceptible to removal from the body by hemodialysis, either due to their physicochemical properties or their large volumes of distribution. For example, despite being primarily renally excreted (approximately 65% of an administered oral dose), digoxin cannot be effectively dialyzed, whereas amiodarone cannot be effectively removed from the blood due to a VOD of approximately 66 L/kg. This large VOD means that most amiodarone is sequestered in compartments other than the intravascular space. In the latter case, hemodialysis would be futile because the volume of blood required to circulate through a dialysis machine would be too large to be practical.
Second, the rate of removal of a drug from the blood must be taken into account. Hemodialysis and hemoperfusion are slow (e.g., generally hours) to generally remove drugs at toxic levels from the bloodstream.
For example, the intoxications of two testbed drugs, amiodarone and amitriptyline, are frequently life threatening because of their severe effects on cardiac function. Accordingly, treatment under these conditions must be initiated immediately or a patient may die. Consequently, hemodialysis or hemoperfusion cannot be used as a treatment for fast acting life threatening drugs such as amiodarone and amitriptyline. In addition, these approaches require the placement of large arterial and venous cannula prior to circulation of blood through the dialysis machine. As a result of its shortcomings, hemodialysis has minimal applications in treating drug toxicity. However, hemodialysis may be applicable for toxic drugs with low volumes of distribution and for those toxins that do not immediately produce life threatening effects.
Another method for treating drug poisonings is the use of specific pharmacological antidotes. However, of the many types of drug poisonings in humans, only a few have identified specific pharmacological antagonists that can be used to quickly and selectively reverse their deleterious physiological effects. Probably the best two examples of effective pharmacological antidotes are the muscarinic-cholinergic and narcotic receptor antagonists, atropine and naloxone, respectively. Atropine blocks the physiological effects of excessive acetylcholine levels on muscarinic receptors. Therefore, it is effective against organophosphate-based insecticides as well as nerve gas agents.
In an analogous manner, naloxone blocks most of the physiological effects (e.g., respiratory depression) of narcotic overdosage. Therefore, it is effective in reversing the physiological effects of potent narcotics such as heroin and fentanyl. Although receptor antagonists are highly efficacious, rapid and specific in reversing these types of life threatening drug poisonings, they do so by preventing access of the agonist to its cellular locus of action (i.e., the receptor). Receptor antagonists neither alter the free blood drug concentration, nor promote its biotransformation to less toxic metabolites and its ultimate excretion from the body. This is clinically important, because deaths have been reported when the biological effects of a receptor antagonist outlives that of the drug toxin.
In contrast to the above situations where life saving measures frequently must be instituted immediately or death may occur, a different type of pharmacological antidote, a biochemical one, may also be used to treat drug toxicity problems that are less emergent in nature. The best-known example of this type of treatment is using N-acetylcysteine to replenish hepatic stores of glutathione in the setting of acetaminophen (Tylenol®) overdosage.
However, high levels of acetaminophen in the blood deplete liver sulfhydryl stores. This, in turn, allows the formation of a highly reactive intermediate, N-acetyl-benzoquinoneimine, that can cause free radical injury to the liver. Acetaminophen toxicity is a slow ongoing process which develops over a period of several hours to days. Accordingly, it is not necessary to treat acetaminophen toxicity with a method which quickly decreases the chemical level to save lives. An effective treatment to acetaminophen overdosage is already available. By replenishing hepatic stores of glutathione using N-acetylcysteine orally or intravenously, the liver can be protected against further injury from toxic metabolites of acetaminophen. However, biochemical antidotes can only be used to treat the narrow class of drugs which result in slow acting toxicity.
Thus, based on the lack of effectiveness of currently available treatments for most drug intoxications, there is a need for new and improved technologies for rapidly and inexpensively reducing the free drug concentration for a wide variety of drugs. Drugs to be treated may be introduced in potentially toxic levels into living organisms as well as onto non-biological surfaces or bodies such as metal or wood.